- This is a resubmission of a competitive renewal of a previous proposal that examined the role of the neurological system in cutaneous wound healing. During the previous funding period, it was demonstrated that the cutaneous sensory neurological system and released neuropeptides were capable of modulating a number of important components of inflammation and wound healing responses in the skin. This application will test the general hypothesis that the sensory nervous system is capable of regulating a number of essential aspects of cutaneous angiogenesis by the release of neuropeptides such as substance P (SP) and calcitonin gene related peptide (CGRP). The released neuropeptides activate specific dermal microvascular endothelial cell (DMEC) neuropeptide receptors to promote angiogenesis. This interaction might play a key role in modulating normal and pathological processes in the skin. The specific aims of this application are: 1) Determine the capacity of specific sensory neuropeptides to modulate DMEC angiogenic responses directly; 2) determine the capacity of activated neurites to modulate DMEC angiogenic responses directly; 3) determine the capacity of the cutaneous neurological system to modulate angiogenesis in the skin; and 4) determine the capacity of the cutaneous neurological system to modulate angiogenesis in wound healing of the skin. The role of specific neuropeptides and their respective receptors in modulating angiogenesis will be determined in vitro and in vivo utilizing both murine and human model systems. In vitro DMEC angiogenesis responses will be assessed by measuring microvascular endothelial cell (a) proliferation, (b) chemotaxis/ chemokinesis, (c) matrix metalloproteinase (MMP)/tissue inhibitor of MMP production, (d) endothelial cell derived angiogenic factor production, and (e) endothelial tube formation/sprouting. The ability of activated sensory neurons co-cultured with DMEC to induce angiogenic activities will be determined. In vivo cutaneous angiogenic responses to topical capsaicin, injected neuropeptides, in normal and during wound healing will be measured by direct vessel counts and computer-assisted image analysis after immunostaining. These studies will further basic understanding of the role of the nervous system in angiogenesis and could lead to novel therapies for a wide range of cutaneous processes including inflammation, wound healing, and neoplasia.